One of the most consistent findings in functional brain imaging studies of schizophrenia is failure to activate prefrontal and temporal cortical regions when challenged by cognitive tasks. However, it is unclear if this 'hypometabolic' response is reflective of primary cortical dysfunction or secondary to factors involved in task performance. To resolve this issue, we propose to examine the effects of two cortical challenges, one biochemical and one cognitive, on local cerebral blood flow (CBF) in schizophrenic patients and matched healthy controls with H2/15O/PET. The biochemical challenge is acute glucose deprivation induced by pharmacologic doses of the glycolytic inhibitor 2-deoxyglucose (2DG). The cognitive challenge is a verbal fluency task which will be administered in a manner that minimizes performance differences between groups. The hypothesis to be tested is that schizophrenic patients, in comparison to controls, will have decreased CBF in prefrontal cortex and temporal lobes following exposure to both biochemical and cognitive challenges. In additon, in collaboration with the Laboratory of Cerebral Metabolism, studies are being conducted to elucidate the mechanisms of 2DG on CBF. To date, dose finding studies in healthy vounteers have been completed and a bolus dose of 40mg/kg of 2DG will be used in the imaging studies. We have completed CBF studies of 8 healthy controls and these data are currently being analyzed. Providing the healthy volunteer data demonstrates cortical activation, we will begin scanning schizophrenic patients this summer.Preclinical studies are examing the role of nitric oxide, electrolyte shifts, pH and catecholamines on 2DG-induced increases in CBF.